Bacterial translocation (BT) is defined as the transfer of microbes from the intestinal lumen to any extra-luminal site in the host. Some BT is probably normal. However, a variety of stresses exaggerate BT and contribute to the pathogenesis of systemic infections. Preliminary data suggest that NO production by enterocytes may play a regulatory role in the pathogenesis of exaggerated BT. In certain pathologic conditions, overproduction of NO may induce cellular injury and lead to enterocyte apoptosis resulting in gut barrier failure and increased BT. The goal of the study is to determine the mechanisms by which NO regulates BT in vivo and in vitro. The study has three specific aims: I) to study the regulation of NOS-2 within the intestine by various factors, including cytokines, luminal contents, and intra-epithelial lymphocytes; II) to determine, using NOS-2 knockout mice and NOS-2 gene-transfer experiments, the mechanisms by which NO regulates transmucosal passage of bacteria; III) to determine the effect of various reactive nitrogen species (RNI) on BT.